The presentation deals with one of the most important signalling pathway that plays key role in inflammation and related diseases like asthma.

1. www.emmamihill.com
Signalling

2. •Introduction : Inflammation
•Physiology of Inflammation
•Introduction to Nf-Kb complex
•Signaling pathways of Nf-Kb
•Role of NF-KB signaling pathway
in asthama

3. Introduction
• Inflammation is the body's attempt at self-
protection; the aim being to remove harmful
stimuli, including damaged cells, irritants, or
pathogens and begin the healing process.
Signs of inflammation
• The four cardinal signs of inflammation --the four
"ORs" -- are:
• Rubor -- redness.
• Tumor -- swelling (puffiness, edema).
• Calor -- heat.
• Dolor -- pain.

4. Physiology of Inflammation
Increased tissue perfusion causes redness (rubor), as more red blood cells pass through
the tissue.Warmth (calor), as blood carries body heat from the body's core to cooler
peripheral tissues.
There is normally a balance between fluid leaving vascular spaces and fluid re-entering
the system. Inflammation shifts this balance, causing accumulation of interstitial fluid.
The fluid build-up which follows this permeability change is called edema and is visible as
puffiness or swelling (tumor). Pain and/or itching (dolor) is caused by direct action on
nerve endings of the chemical agents released during inflammation.

5. www.lhsc.on.ca

6. Nf-Kb introduction
• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B
cells) is a protein complex that controls transcription of DNA.
• In most cells, NF-B complexes are inactive, residing primarily in the
cytoplasm in a complex with any of the family of inhibitory proteins.
When the pathway is activated, the inhibitory protein is degraded
and the NF-B complex enters the nucleus to modulate target gene
expression.
• These factors are involved in the control of a large number of
normal cellular and organism processes, such as immune and
inflammatory responses, developmental processes, cellular
growth, and apoptosis.
hkissamalkha.com

7. Nf-Kb’s structure
• In mammals, the NF-B family is composed of five related transcription
factors: p50, p52, RelA (aka p65), c-Rel and RelB.
• These transcription factors are related through an N-terminal DNA-
binding/dimerization domain, called the Rel homology domain, through
which they can form homodimers and heterodimers, which bind to a
variety of related target DNA sequences called B sites to modulate gene
expression. Rel/Nf-Kb
RelA, c-Rel and RelB contain C-
terminal transcription activation
domains (TADs), which enable
them to activate target gene
expression.
p50 and p52 do not contain C-
terminal trans activation domains;
therefore, p50 and p52
homodimers can repress
transcription.
**Members of this first class are generally not activators of transcription, except when they
form dimers with members of the second class

8. Nf-Kb’s structure

9. Signaling pathways of Nf-Kb
• Canonical / Classical Pathway
 Binding of ligand to a cell surface
receptor leads to the recruitment of
adaptors to the cytoplasmic domain of the
receptor .
These adaptors in turn recruit I κB kinase
(IKK) complex, which phosphorylates I κB
and targets it for proteasomal degradation
.
The IKK complex consists of two
catalytically active kinases (IKK and IKK)
and a regulatory scaffold protein, NEMO.
IKK and NEMO are required for the
activation of complexes such as p50/RelA,
p50/c-Rel, etc., whereas IKK is relatively
dispensable.

10. Signaling pathways of Nf-Kb
• Non-Canonical / Alternate Pathway
 It is responsible for the activation of
p100/RelB complexes and occurs during the
development of lymphoid organs responsible
for the generation of B and T lymphocytes.
This pathway utilizes an IKK complex that
comprises two IKKα subunits, but not NEMO
.
Receptor binding leads to the activation of
NIK(nf-kb inducing kinases) which
phosphorylates and activates an IKK alpha
complex that in turn phosphorylates the IκB
domain of p100 leading to the liberation of
p52/RelB.
 This heterodimer subsequently translocates
to the nucleus to activate target genes.

11. eoncosurg.com
IkB degradation
Diverse functions
Response to numerous stimulus
Rapid and transient
No IkB degradation dependent
Slow and persistent
Respond to specific (TNFR motiff based) signal
Specific functions

13. • INTRODUCTION
Asthma is a chronic lung disease that inflames and narrows the airways.
Asthma causes recurring periods of wheezing (a whistling sound when
you breathe), chest tightness, shortness of breath, and coughing.
http://www.nhlbi.nih.gov/

14. • Asthma is associated with the increased expression of several
important inflammatory proteins, including cytokines and
adhesion molecules.
• Expression of these proteins positively correlates with NF-κB
activation in bronchial biopsies from asthmatic patients.
• The increase in these processes involve increased
transcription of inflammatory genes that are known to be
regulated by transcription factors NF-κB

15. Nf kb gets activated by various stimuli, including cytokines, reactive oxygen
species and microorganisms that induce the degradation and release of I-
κB from p50 and p65 complex.

16. • It is responsible for airway obstruction and hyper-reactivity.
• The histamine involved in this process promote inflammation by
inducing NF-κB activation, which activates genes whose proteins
promote inflammation and the maturation of T cells in asthma
patients .
Histamine
from
allergens
NF-kB activation Signaling pathway Gene
activation
Proteins generationInflammation and
maturation of T
cells
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17. • The improper functioning of NF-κB in apoptosis leads
to recruitment of immune cells which in turn leads to
perpetuated inflammatory responses.
• NF-κB stimulates the expression and activity of anti apoptotic
protein Bcl-2, while inhibiting apoptotic protein Bax.
• This suggests a progressive decrease in apoptosis and an
increase in the survival of lymphocytes that infiltrate the lung
of patients with severe asthma.
Bcl-2
Bcl-2
Bax
Bax
Apoptosis
a. Normal cells
b. Cells with improper Nf-kB

18. Corticosteroids enter the cell, bind to the glucocorticoid receptor (GR) in the cytoplasm and
translocate to the nucleus, where the transcription of target genes is initiated.
Many genes contain glucocorticosteroid response elements (GREs) in their promoters. Through
transactivation, binding of the activated glucocorticoid receptor homodimer to a GRE in the
promoter region of steroid-sensitive genes leads to the transcription of genes encoding anti-
inflammatory mediators.

19. Through transrepression, the glucocorticoid receptor–corticosteroid complex interacts with
large co-activator molecules with intrinsic histone acetyltransferase (HAT) activity which are
activated by pro-inflammatory transcription factors (such as NF-B and AP1), thus switching
off expression of the inflammatory genes that are activated by these transcription factors.
RNA pol II, RNA polymerase II.

20. 1. “An overview of NF-κB signaling in health and disease” by
Claudie Hooper
2. “NF-B and the immune response” ; M S Hayden, A
P West and S Ghosh
3. “The Nuclear Factor NF-κB Pathway in Inflammation”;
Toby Lawrence
4. “Signaling to NF-kappaB” ;Hayden MS, Ghosh S.
5. “NF-kB Transcription Factors “;Dr. Thomas Gilmore
6. “The involvement of NF-κB Transcription factor in asthma”
Guadalupe Rico-Rosillo ,Gloria Bertha Vega-Robledo
7. Anti-inflammatory actions of corticosteroids.
FROM THE ARTICLE:Treatment strategies for allergy and
asthma ; Stephen T. Holgate & Riccardo Polosa

21. oilersnation.com